Zolpidem Tartrate Sublingual Tablets (Intermezzo®) CIV
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.
A low-dose sublingual formulation of Zolpidem has been approved by the FDA for the management of middle-of-the-night (MOTN) awakening. Zolpidem, marketed as Ambien, was originally approved in 1992. The new formulation is marketed by Transcept Pharmaceuticals as Intermezzo.
Sublingual zolpidem is indicated for as needed use in the treatment of MOTN awakening followed by difficulty returning to sleep.1
The recommended dose is 1.75 mg (women) or 3.5 mg (men) given sublingually once per night as needed.1 The doses are gender specific because women clear the drug at a lower rate then men. Zolpidem should not be taken if there is less than 4 hours remaining before planned awakening.
Zolpidem is available as 1.75 mg and 3.5 mg sublingual tablets.
This is the first drug/formulation approved for the indication of MOTN awakening followed by difficulty returning to sleep.
Sublingual zolpidem shares the same warning and precautions regarding central nervous system depression, abnormal thinking, and behavioral changes as regular strength zolpidem, as well as other sedative-hypnotics. Behaviors may include "sleep-driving," preparing and eating food, making phone calls, etc.
Zolpidem tartrate has been formulated as a sublingual tablet for disintegration and absorption via the oral mucosa. The safety and efficacy was studied in two randomized, double-blind, placebo-controlled studies.1,2 Study one was based on scheduled dosing (n = 82) and study two was based on as-needed dosing (n = 295). Study one was a randomized, double-blind, placebo-controlled, three-way crossover study in adult subjects with DSM-IV primary insomnia and polysomnography and sleep diary confirmed MOTN awakening.2 Subjects were required to have MOTN awakening characterized by at least three awakenings per week and needing at least 30 minutes to fall back to sleep. Each subject received three 2-night treatment periods of 1.75 mg, 3.5 mg, and placebo with a 5-to-12-day washout period. The primary efficacy endpoint was mean latency to persistent sleep (LPS) following MOTN awakening comparing 3.5 mg and placebo. Secondary endpoints included total sleep time (TST), subjects' rating of quality of sleep, safety as assessed by adverse events, vital signs, laboratory parameters, and next morning residual effects. At each treatment night, subjects were awakened 4 hours after initial lights out regardless of the sleep stage. LPS values were 28.1, 16.9, and 9.7 minutes, respectively, for placebo, 1.75 mg, and 3.5 mg of sublingual zolpidem. Sleep onset was significantly faster with both active doses compared to placebo and 3.5 mg was faster than 1.75 mg. TST values were 183, 198, and 209 minutes with similar statistical differences. Zolpidem 3.5 mg showed the best improvement in sleep quality. Next-morning residual effects and adverse events were not significantly different between zolpidem and placebo.
In the second study where sublingual zolpidem (3.5 mg) or placebo was given on an as-needed basis, zolpidem showed a significantly shorter patient-estimated time to fall back to sleep after MOTN awakening.1 The daytime pharmacodynamics and pharmacokinetics of sublingual zolpidem were assessed in a single-dose, randomized, double-blind, placebo-controlled, crossover study.3 Three doses (1 mg, 1.75 mg, and 3.5 mg) were compared to placebo. Subjects were randomized to dosing sequences that included four treatments separated by 5-12 days. Treatment was given approximately 1 hour after awakening and assessed over 5 hours. Daytime sedation was assessed objectively by the Digit Symbol Substitution Test and subjectively by the Visual Analog Scale. Blood levels of zolpidem were measured up to 12 hours post-dose. Significant sedation was evident in 20 minutes and lasted up to 90 minutes for the 3.5 mg dose. There was no difference among the treatments 4-5 hours post dose. Subjective self-rated significant sedation for the 1.75 mg and 3.5 mg doses compared to placebo was from 20 minutes through 2 hours. Pharmacodynamics seem to mirror the pharmacokinetics as plasma levels above 20 -25 ng/mL were reached within 20 minutes and maintained for up to 4 hours.
Insomnia is a common disorder characterized by difficulty falling asleep, maintaining sleep, or early morning awakening.4 More than a third of adults experience MOTN awakening three or more nights per week.2 Previously approved medications for insomnia are directed at sleep initiation and maintenance. A zolpidem tartrate sublingual tablet is the first drug approved for MOTN awakening.
1. Intermezzo Prescribing Information. Richmond, CA: Transcept Pharmaceuticals, Inc; November 2011.
2. Roth T, et al. Low-dose sublingual zolpidem tartrate is associated with dose-related improvement in sleep onset and duration in insomnia characterized by middle-of-the-night (MOTN) awakenings. Sleep 2008;31:1277-1284.
3. Roth T, et al. Daytime pharmacodynamic and pharmacokinetic evaluation of low-dose sublingual transmucosal zolpidem hemitartrate. Hum Psychopharmacol 2008;23:13-20.
4. Ohayon MM, Reynolds CF. Epidemiological and clinical relevance of insomnia diagnosis algorithms according to the DSM-IV and the International Classification of Sleep Disorders (ICSD). Sleep Med 2009;10:952-960.